Mitochondrial modulation decreases the bortezomib-resistance in multiple myeloma cells

Abstract

Multiple myeloma (MM) is an incurable hematological malignancy that causes most patients to eventually relapse and die from their disease. The 20S proteasome inhibitor bortezomib has emerged as an effective drug for MM treatment; however, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. We evaluated the involvement of mitochondria in resistance to bortezomib-induced cell death in two different MM cell lines (bortezomib-resistant KMS20 cells and bortezomib-sensitive KMS28BM cells). Indices of mitochondrial function, including membrane potential, oxygen consumption rate and adenosine-5′-triphosphate and mitochondrial Ca 2+ concentrations, were positively correlated with drug resistance of KMS cell lines. Mitochondrial genes including CYPD, SOD2 and MCU were differentially expressed in KMS cells. Thus, changes in the expression of these genes lead to changes in mitochondrial activity and in bortezomib susceptibility or resistance, and their combined effect contributes to differential sensitivity or resistance of MM cells to bortezomib. In support of this finding, coadministration of bortezomib and 2-methoxyestradiol, a SOD inhibitor, rendered KMS20 cells sensitive to apoptosis. Our results provide new insight into therapeutic modalities for MM patients. Studying mitochondrial activity and specific mitochondrial gene expression in fresh MM specimens might help predict resistance to proapoptotic chemotherapies and inform clinical decision-making. What's new? While proteasome inhibitor bortezomib is an effective drug for multiple myeloma (MM), therapy can cause both intrinsic and acquired resistance. Here the authors evaluated the involvement of mitochondria using bortezomib-resistant and -sensitive MM cell lines. Indices of mitochondrial function, including membrane potential, oxygen consumption rate, and adenosine-5'-triphosphate and mitochondrial Ca2+ concentrations, were positively correlated with drug resistance. Mitochondrial genes such as CYPD, SOD2, and MCU were also differentially expressed, contributing to the differential mitochondrial activity and sensitivity to bortezomib. Studying mitochondrial activity and specific mitochondrial gene expression in MM specimens might help predict resistance to pro-apoptotic chemotherapies and inform clinical decision-making. Copyright © 2013 UICC.